Simvastatin is a first-generation statin used for LDL reduction and ASCVD prevention.

It is less potent than Atorvastatin and Rosuvastatin, and carries a higher drug–drug interaction risk due to CYP3A4 metabolism.

The 80 mg dose is no longer recommended due to increased myopathy risk.

Primary Target:

• HMG-CoA reductase (rate-limiting step in hepatic cholesterol synthesis)

Physiologic Effects:

• ↓ Hepatic cholesterol production
• ↑ LDL receptor expression
• ↑ Circulating LDL clearance

Net Effect:

• Moderate LDL reduction
• Reduced cardiovascular events

LDL lowering is dose-dependent.

• Hyperlipidemia
• ASCVD prevention
• Secondary prevention after:
  • Myocardial Infarction
  • Ischemic Stroke

Low-Intensity:

• 10 mg daily

Moderate-Intensity:

• 20–40 mg daily

Important:

• 80 mg dose should NOT be initiated
• Use 80 mg only if patient has tolerated long-term without adverse effects

Dose selection is based on ASCVD risk category.

• Lipophilic statin
• Extensively metabolized by CYP3A4
• Higher drug–drug interaction burden
• Shorter half-life compared to Atorvastatin and Rosuvastatin

Due to lipophilicity, may have greater muscle penetration.

Muscle:

• Myalgias
• Myositis
• Increased risk of rhabdomyolysis (dose-dependent)

Hepatic:

• Mild ALT elevation

Metabolic:

• Slight increase in diabetes risk

Myopathy risk increases with:

• High dose (especially 80 mg)
• CYP3A4 inhibitors
• Combination with Fibrates (especially Gemfibrozil)

High interaction risk due to CYP3A4 metabolism.

Avoid or use caution with:

• Macrolide antibiotics
• Azole antifungals
• Protease inhibitors
• Grapefruit juice

Higher myopathy risk when combined with:

• Fibrates
• Niacin
• Other CYP3A4-metabolized statins

Compared to:

• Rosuvastatin — higher interaction burden
• Pravastatin — significantly higher interaction burden

• Lipid panel (4–12 weeks after initiation)
• Baseline liver enzymes
• Monitor for muscle symptoms

CK only if symptomatic.

Compared to Atorvastatin:

• Less potent
• Higher CYP interaction risk
• Lower LDL reduction at maximal dose

Compared to Rosuvastatin:

• Significantly less potent
• More drug interactions
• Shorter half-life

Clinical Role:

• Appropriate moderate-intensity option
• Less favored when high-intensity therapy is indicated

• Avoid initiating 80 mg dose
• CYP3A4 interactions are clinically significant
• Lipophilic statin with moderate potency
• Consider alternative statins in polypharmacy patients
• Still effective for moderate-risk ASCVD prevention

• Statins
• Atorvastatin
• Rosuvastatin
• Pravastatin
• Cardiovascular Pharmacology